HLA encoded class II alloantigens are polymorphic cell surface glycoproteins that are important in immune responses and function in the restriction of T cell recognition of antigen. Certain D region alloantigens are associated with increased disease risk for virtually all of the described human autoimmune diseases. Despite these known associations the means by which certain D region alloantigens confer increased disease risk is unknown. Over 90% of the autoimmune diseases effect predominantly women with ratios up to 9:1 and higher. Although sex steroids may play some role they cannot alone explain the female predominance of autoimmune diseases. Reproduction is clearly a process that is relevant to immunity since the unborn child carries genetic information that is foreign to the mother. Anti-fetal HLA responses occur during normal pregnancy and are in unknown ways important to the maintenance of pregnancy since their absence is associated with recurrent fetal loss. Rheumatoid arthritis is an autoimmune disease of special interest since it remits during pregnancy in the majority of women only to recur postpartum. Preliminary work by the applicant suggests that maternal anti-fetal HLA response is important in the pregnancy induced remission of RA. The studies described will examine HLA-D region alloantigens in RA patients with serological and cellular methods and include the use of T cell clones to define epitopes within serologically defined DR specificities. D region epitopes will be examined in relationship to clinical disease and anti-HLA D region alloantigen response will be evaluated as potentially immunomodulatory for RA disease activity. In addition, the broader question of reproductive performance, autoimmune disease, and HLA class II alloantigens will be addressed by examination of normal women and reproductive history as well as women with RA with the benefit of both populations derived from an ongoing case-control study of prospectively and newly diagnosed cases of rheumatoid arthritis in women currently in progress in King County, Washington.